How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
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Rania Mahmoud
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway and passively by the nonsaturable paracellular pathway
Active uptake of phosphate in the transcellular pathway is facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b
In patients with ESKD, the transcellular pathway was found to saturate above a luminal concentration of approximately 6 mg/dl (2 mM/l).67 Calculations based on gastric volume determined that the dietary phosphate intake of up to 2500 mg/d associated with a typical Western diet would result in luminal phosphorus concentrations of approximately 55 to 110 mg/dl (18–36 mmol/lfar exceeding the maximum amount of phosphorus that can be transported by the transcellular pathway. New therapies targeting intestinal phosphate absorption pathways have been developed. Phase 1 trialsof the novel drug EOS789, an inhibitor of the sodiumphosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis
Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters. Multiple small clinical trials in patients with ESKD have reported reduction in serum phosphorus concentration, but larger studies are lacking to support widespread use.
Another novel drug that targets a phosphate absorption pathway is tenapanor, an investigational,nonbinder therapy that inhibits the sodium/hydrogenexchanger isoform 3 (NHE3) in the GI tract. Inhibitionof NHE3 blocks paracellular phosphate permeability byreducing sodium absorption and causing conformational changes in tight junction proteins.72 Tenapanor has been found to efficiently reduce phosphorus levels in multiple clinical trials .The most frequently reported adverse event was diarrhea, A separate long-term study supports the tolerability of tenapanor: rates of serious adverseevents were higher in patients treated with sevelamer carbonate (16.4%–23.4%) versus tenapanor (11.2%– 17.4%) across all study periods
No clinically meaningful changes in serum calcium, bicarbonate, chloride, potassium, sodium, or glucose were observed. It isadministered as 1 tablet taken twice a day, which maysignificantly decrease the pill burden for patients with hyperphosphatemia who currently need to take approximately 9 phosphate binder pills each day
In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway and passively by the nonsaturable paracellular pathway.
Active uptake of phosphate in the transcellular pathway is facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b.
New therapies targeting intestinal phosphate absorption pathways have been developed.
Phase 1 trials of the novel drug EOS789, an inhibitor of the sodium phosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis.
Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters. Multiple small clinical trials in patients with ESKD have reported reduction in serum phosphorus concentration, but larger studies are lacking to support widespread use.
Another novel drug that targets a phosphate absorption pathway is Tenapanor, nonbinder therapy that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in the GI tract. Inhibition of NHE3 blocks paracellular phosphate permeability by reducing sodium absorption and causing conformational changes in tight junction proteins. Tenapanor has been found to efficiently reduce phosphorus levels in multiple clinical trials. The most frequently reported adverse event was diarrhea. A separate long-term study supports the tolerability of tenapanor: rates of serious adverse events were higher in patients treated with sevelamer carbonate (16.4%–23.4%) versus tenapanor (11.2%–17.4%) across all study periods. No clinically meaningful changes in serum calcium, bicarbonate, chloride potassium, sodium, or glucose were observed.
Administered as 1 tablet taken twice a day, which may significantly decrease the pill burden for patients with hyperphosphatemia who currently need to take approximately 9 phosphate binder pills each day.
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway and passively by the nonsaturable paracellular pathway.
Active uptake of phosphate in the transcellular pathway is facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b.
In patients with ESKD, the transcellular pathway was found to saturate above a luminal concentration of approximately 6 mg/ Calculations based on gastric volume determined that the dietary phosphate intake of up to 2500 mg/d associated with a typical Western diet would result in luminal phosphorus concentrations of approximately 55 to 110 mg/dl (18–36 mmol/l) far exceeding the maximum amount of phosphorus that can be transported by the transcellular pathway.
EOS789 New therapies targeting intestinal phosphate absorption pathways have been developed, an inhibitor of the sodium phosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis.
tenapanor,another novel drug that targets a phosphate absorption pathway is an investigational, nonbinder therapy that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in the GI tract.
Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters, no significant reductions in phosphorus were observed in a 12-month trial of nondialysis patients with CKD treated with nicotinamide.
In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway and passively by the nonsaturable paracellular pathway.Active uptake of phosphate in the transcellular pathway is facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b.In patients with ESKD, the transcellular pathway was found to saturate above a luminal concentration of approximately 6 mg/ dl (2 mM/l).
New therapies targeting intestinal phosphate absorption pathways have been developed. Phase 1 trials of the novel drug EOS789, an inhibitor of the sodium phosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis.
Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters, is another potential hyperphosphatemia treatment.Nevertheless, no significant reductions in phosphorus were observed in a 12-month trial of nondialysis patients with CKD treated with nicotinamide.Multiple small clinical trials in patients with ESKD have reported reduction in serum phosphorus concentration, but larger studies are lacking to support widespread use.
Another novel drug that targets a phosphate absorption pathway is tenapanor, an investigational, nonbinder therapy that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in the GI tract. Inhibition of NHE3 blocks paracellular phosphate permeability by reducing sodium absorption and causing conformational changes in tight junction proteins.7Tenapanor has been found to efficiently reduce phosphorus levels in multiple clinical trials.
Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control; in the intestine, the phosphate is absorbed actively by saturable transcellular and passively by nonsaturable paracellular.
this mechanism of phosphate uptake is ease by NaPI2b. new therapies(novel drug EOS789) targeting inhibiting phosphate sodium contransport.
Phosphorus absorption in GIT of CKD pts behaves as reversed physiology of normal subjects, where mainly paracellular passive absorption (via tight junctions) under concentration gradient takes a place.
To a lesser extent it follows saturable transcellular active transport (NaPi2b cotransporter).
So new therapies targeted these mechanisms:
EOS789: reduce transcellular phosphorus absorption (inhibit NaPi2b cotransporter), phase 1trial on HD pts revealed encouraging results, safety and tolerability.
Nicotineamide: reduce transcellular phosphorus absorption (inhibit NaPi2b cotransporter), show positive results in HD pts, but non significant results in 12months trials in CKD5-ND pts, larger studies are lacking to support widespread use.
tenapanor: reduce paracellular phosphorus absorption (inhibit NHE3), advantage of low pill burden (1tab bid), causes diarrhea, but generally tolerable.
1- EOS789 molecule acts on active transcellular pathway by inhibition of sodium phosphorus co transporter . 2- tenapanor acts on passive paracellular pathways .
1- EOS789 molecule acts on active transcellular pathway by inhibition of sodium phosphorus co transporter
2- tenapanor acts on passive paracellular pathways
Paracellular and transcellular pathways discovery and use of EOS789 and Tenapanor.
Tenapanor:decrease the number of pills/long-acting effect
Combining therapy:success in maintaining normal targeted phosphorus levels.
In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway(facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b) and passively by the nonsaturable paracellular pathway.
In patients with ESKD, the transcellular pathway was found to saturate above a luminal concentration of approximately 6 mg/ dl (2 mM/l).
Studies in humans and animals revealed that passive phosphate absorption by the paracellular pathway occurs along concentration gradients through tight junction complexes (e.g., claudins and occludins) between cell membranes.
Animal data reveal that 65% to 80% of intestinal phosphate absorption occurs paracellularly,and human data support the dominance of the paracellular pathway, particularly when phosphate concentrations are high.
New therapies targeting intestinal phosphate absorption pathways have been developed;
1-Phase 1 trials of the novel drug EOS789(safe,well tolerated and effective), an inhibitor of the sodium phosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis.
2-Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters, is another potential hyperphosphatemia treatment.
3-Tenapanor, an investigational, nonbinder therapy that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in the GI tract. Inhibition of NHE3 blocks paracellular phosphate permeability by reducing sodium absorption and causing conformational changes in tight junction proteins.
The novel therapy depends on the prevent of intstinal absorption of po4 and there are two different ones the 1st Eos789 pley in inhibiton of Napo4 exchange and get synergistic effect when added with sevelamer
the other one tenapanor also blocks NHE3 thats inhibiton of Napo4 permiability and absorption
In the intestine the phosphate absorbed actively through transcellular saturable pathway and passively by non saturable paracellular pathway.
The phosphate uptake through the active transcellular pathway by type 2 dependant sodium phosphate cotransporter NaPi2b.
Studies show that the passive paracellular pathway occur through concentration gradient through tight junctions Claudine and occludine between cell membrane. The human study show dominance of paracellular transport specially when phosphate is high.
New drugs that target phosphate transport example
*ESO789 which inhibit Npi2b and show encouraging results in which phosphate absorption decrease
*nicotinamide also block this channel and show promising results
*Tenapanor which inhibit sodium hydrogen 3 exchanger NHE3 so prevent paracellular phosphate absorption through decreasing sodium absorption which lead to changes in the tight junction between cell membrane and decrease phosphate absorption.
Studies show effective reduction of phosphate absorption through the use of this drug.
Paracellular and transcellular pathways discovery paved the way for the use of EOS789 and Tenapanor. Tenapanor showed good results, helped decrease the number of pills and has a long-acting effect, so twice daily is a good option. Combining therapy showed increased success in maintaining normal targeted phosphorus levels.
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control? The dietary phosphate is absorbed in the jejunum. At the subcellular levels, this absorption occurs through two pathways 1- Passive non saturable Paracellular, Na+ independent pathway the study revealed that passive occurs along concentration gradients through tight junction complexes (eg claudin and occludins )between cell membrane animal data revealed that 65% to 80%of intestinal phosphate absorption occurs paracellularly and human data support the dominance of paracellular pathway particularly when phosphate concentration are high 2- Active saturable Transcellular, Na+ dependent pathway via sodium phosphate cotransporter (NaPi-IIb) This new understanding of phosphate absorption pass ways
Lead to developed new novel dugs
1-Acting on active pathway a- EOS789 Drug an inhibitor of the sodium phosphate cotransporter Na pi 2b, and Pi t -1 b- Nicotinamide also seem to reduce phosphate -specific transcellular permeability by inihibition gut Napi 2b cotransporter is another potential hyperphosphatemia treatment but lacking large studies to support wide spreads use 2-acting on passive pathway Tenapnor drug is another novel drug targeted phosphate absorption pass way mechanism of action inhibits the sodium /hydrogen exchanger isoform 3(NHE3) in the GI tract inhibition of NHE3 blocks paracellular phosphate permeability by reducing sodium absorption and causing conformational changes in ight junctional proteins Tenapanor has been found to efficiently reduce phosphate level s in multiple clinical trial All these novel drugs need multiple trial , solid study and comparison with other binders phosphate medication
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
Tow main intestinal pathways of phosphate absorption are therapeutic targets: 1.Transcellular pathway:
~ 20% of PO4 is absorbed by this pathway
active process
Na Pi 2b co-transporter on the luminal border responsible for reabsorption
Therapeutic targets to block PO4 absorption through this pathway:1) EOS789 2) Nicotinamide
2.Paracellular pathway:
This a passive process, and non saturable
Responsible for 65 -80% of intestinal phosphate absorption
Absorption occurs along the concentration gradients through tight complexes between cell membrane.
Therapeutic targets to block PO4 absorption through this pathway: Mainly tenapanor which blocks NHE3 by reducing Na absorption and causing conformational changes in tight junction proteins
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?dietary phosphate is absorbed by
1-transcellular pathway (active process )
facilitated by the type 2 NaPi2b which saturated in patients with ESKD
2-paracellular patheay (passive ) non saaturated and occur through concentration gradients through tight junction complex between cell membranes
65% to 80 % of intestinal phosphate absorption occurs paracellularly
so new therapies targeting intestinal phosphate absorption pathways phase 1 trials of the novel drug an inhibitorof sodium phosphate cotransporter
tenapanor :inhibit the sodium /hydrogen exchanger in GI tract (paracellular patheay )
By blocking the NaHExchanger3 with tenapanor, the paracellular pathway which account for 60-80% of phosphat absorption is blocked or not more so effective.
This will lead to decreased phosphate absorption in gut. Tenapanor could be taken 2 time daily what lead to better adherence. In the study done patient could decrease their phosphate binders from 15 tablet a day to just 3.
That led to better compliance and better phosphate control.
The transcellular way through blocking NaPi2b with EOS789 led also to benefits.
There is an additive effect when we combine these drugs with phosphate binders.
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
there is 2 main pathways for phosphate absorption as following :
1- Paracellular pathway: this is a passive process, according to the concentration gradient and it is responsible for about 80 % of intestinal phosphate absorption.it involves some proteins in the tight junctions between the colonic mucosal epithelial cells as Claudins. this pathway can be blocked by Tenapanor that enhance Na and water secretion and therefore decrease the transit time for passive absorption. 2- Transcellular pathway : this is an active process, against the concentration gradient and it is responsible for about 20 % of intestinal phosphate absorption. it involve a specific Na-Phosphate co transporter that can be blocked by the new phosphate binder, EOS789
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
Tow main intestinal pathways of phosphate absorption are therapeutic targets:
1.Transcellular pathway:
This is active process facilitated by Na Pi 2b co-transporter on the luminal border.
It is saturable, and the maximum luminal PO4 concentration to be carried by this co-transporter is 6 mg/dl
~ 20% of PO4 is absorbed by this pathway
It is a secondary pathway
Therapeutic targets to block PO4 absorption through this pathway:1) EOS789 2) Nicotinamide
2.Paracellular pathway:
This a passive process, and non saturable
Responsible for 65 -80% of intestinal phosphate absorption
It is the primary pathway
Absorption occurs along the concentration gradients through tight complexes between cell membranes such as claudins and occludins
Therapeutic targets to block PO4 absorption through this pathway: Mainly tenapanor which blocks NHE3 by reducing Na absorption and causing conformational changes in tight junction proteins
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
Here is a suggested answer:
In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway and passively by the nonsaturable paracellular pathway.
Active uptake of phosphate in the transcellular pathway is facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b.
New therapies targeting intestinal phosphate absorption pathways have been developed.
Phase 1 trials of the novel drug EOS789, an inhibitor of the sodium phosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis.
Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters. Multiple small clinical trials in patients with ESKD have reported reduction in serum phosphorus concentration, but larger studies are lacking to support widespread use.
Another novel drug that targets a phosphate absorption pathway is Tenapanor, nonbinder therapy that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in the GI tract. Inhibition of NHE3 blocks paracellular phosphate permeability by reducing sodium absorption and causing conformational changes in tight junction proteins. Tenapanor has been found to efficiently reduce phosphorus levels in multiple clinical trials. The most frequently reported adverse event was diarrhea. A separate long-term study supports the tolerability of tenapanor: rates of serious adverse events were higher in patients treated with sevelamer carbonate (16.4%–23.4%) versus tenapanor (11.2%–17.4%) across all study periods. No clinically meaningful changes in serum calcium, bicarbonate, chloride potassium, sodium, or glucose were observed.
Administered as 1 tablet taken twice a day, which may significantly decrease the pill burden for patients with hyperphosphatemia who currently need to take approximately 9 phosphate binder pills each day.
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway and passively by the nonsaturable paracellular pathway.
Active uptake of phosphate in the transcellular pathway is facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b.
In patients with ESKD, the transcellular pathway was found to saturate above a luminal concentration of approximately 6 mg/ Calculations based on gastric volume determined that the dietary phosphate intake of up to 2500 mg/d associated with a typical Western diet would result in luminal phosphorus concentrations of approximately 55 to 110 mg/dl (18–36 mmol/l) far exceeding the maximum amount of phosphorus that can be transported by the transcellular pathway.
EOS789 New therapies targeting intestinal phosphate absorption pathways have been developed, an inhibitor of the sodium phosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis.
tenapanor,another novel drug that targets a phosphate absorption pathway is an investigational, nonbinder therapy that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in the GI tract.
Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters, no significant reductions in phosphorus were observed in a 12-month trial of nondialysis patients with CKD treated with nicotinamide.
In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway and passively by the nonsaturable paracellular pathway.Active uptake of phosphate in the transcellular pathway is facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b.In patients with ESKD, the transcellular pathway was found to saturate above a luminal concentration of approximately 6 mg/ dl (2 mM/l).
New therapies targeting intestinal phosphate absorption pathways have been developed. Phase 1 trials of the novel drug EOS789, an inhibitor of the sodium phosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis.
Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters, is another potential hyperphosphatemia treatment.Nevertheless, no significant reductions in phosphorus were observed in a 12-month trial of nondialysis patients with CKD treated with nicotinamide.Multiple small clinical trials in patients with ESKD have reported reduction in serum phosphorus concentration, but larger studies are lacking to support widespread use.
Another novel drug that targets a phosphate absorption pathway is tenapanor, an investigational, nonbinder therapy that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in the GI tract. Inhibition of NHE3 blocks paracellular phosphate permeability by reducing sodium absorption and causing conformational changes in tight junction proteins.7Tenapanor has been found to efficiently reduce phosphorus levels in multiple clinical trials.
Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control; in the intestine, the phosphate is absorbed actively by saturable transcellular and passively by nonsaturable paracellular.
Phosphorus absorption in GIT of CKD pts behaves as reversed physiology of normal subjects, where mainly paracellular passive absorption (via tight junctions) under concentration gradient takes a place.
To a lesser extent it follows saturable transcellular active transport (NaPi2b cotransporter).
So new therapies targeted these mechanisms:
1- EOS789 molecule acts on active transcellular pathway by inhibition of sodium phosphorus co transporter .
2- tenapanor acts on passive paracellular pathways .
Phosphate Na cotransporter targeted by EOS789 ( transcellular )
Phosphate Na cotransporter targeted by nicotinamide ( transcellular)
Tenapanor inihibits NHE3 therby reducing paracellular PO4 absorption
1- EOS789 molecule acts on active transcellular pathway by inhibition of sodium phosphorus co transporter
2- tenapanor acts on passive paracellular pathways
knowledge of Intestinal phosphate absorption pathways paved the way for novel therapies of phosphate control
Paracellular and transcellular pathways discovery and use of EOS789 and Tenapanor.
Tenapanor:decrease the number of pills/long-acting effect
Combining therapy:success in maintaining normal targeted phosphorus levels.
In the intestine, dietary phosphate is absorbed actively by the saturable transcellular pathway(facilitated by the type II sodium-dependent phosphate cotransporter NaPi2b) and passively by the nonsaturable paracellular pathway.
In patients with ESKD, the transcellular pathway was found to saturate above a luminal concentration of approximately 6 mg/ dl (2 mM/l).
Studies in humans and animals revealed that passive phosphate absorption by the paracellular pathway occurs along concentration gradients through tight junction complexes (e.g., claudins and occludins) between cell membranes.
Animal data reveal that 65% to 80% of intestinal phosphate absorption occurs paracellularly, and human data support the dominance of the paracellular pathway, particularly when phosphate concentrations are high.
New therapies targeting intestinal phosphate absorption pathways have been developed;
1-Phase 1 trials of the novel drug EOS789(safe,well tolerated and effective), an inhibitor of the sodium phosphate cotransporter NaPi-2b, PiT-1, and PiT-2, revealed encouraging results in patients receiving hemodialysis.
2-Nicotinamide, which seems to reduce phosphate-specific transcellular permeability by inhibiting gut NaPi2b cotransporters, is another potential hyperphosphatemia treatment.
3-Tenapanor, an investigational, nonbinder therapy that inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) in the GI tract. Inhibition of NHE3 blocks paracellular phosphate permeability by reducing sodium absorption and causing conformational changes in tight junction proteins.
The novel therapy depends on the prevent of intstinal absorption of po4 and there are two different ones the 1st Eos789 pley in inhibiton of Napo4 exchange and get synergistic effect when added with sevelamer
the other one tenapanor also blocks NHE3 thats inhibiton of Napo4 permiability and absorption
Novel drug therapy for hyperphosphatemia (paracellular pathways
2. Tenapanor
So, the new novel drugs;
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
there are tow intestinal pathways of phosphate absorption are therapeutic targets:
1.Transcellular active pathway:
block PO4 absorption through this pathway:
EOS789 and Nicotinamide
2.Paracellular passive pathway:
block PO4 absorption through this pathway:
tenapanor blocks NHE3 by reducing Na absorption .
In the intestine the phosphate absorbed actively through transcellular saturable pathway and passively by non saturable paracellular pathway.
The phosphate uptake through the active transcellular pathway by type 2 dependant sodium phosphate cotransporter NaPi2b.
Studies show that the passive paracellular pathway occur through concentration gradient through tight junctions Claudine and occludine between cell membrane. The human study show dominance of paracellular transport specially when phosphate is high.
New drugs that target phosphate transport example
*ESO789 which inhibit Npi2b and show encouraging results in which phosphate absorption decrease
*nicotinamide also block this channel and show promising results
*Tenapanor which inhibit sodium hydrogen 3 exchanger NHE3 so prevent paracellular phosphate absorption through decreasing sodium absorption which lead to changes in the tight junction between cell membrane and decrease phosphate absorption.
Studies show effective reduction of phosphate absorption through the use of this drug.
Paracellular and transcellular pathways discovery paved the way for the use of EOS789 and Tenapanor. Tenapanor showed good results, helped decrease the number of pills and has a long-acting effect, so twice daily is a good option. Combining therapy showed increased success in maintaining normal targeted phosphorus levels.
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
The dietary phosphate is absorbed in the jejunum. At the subcellular levels, this absorption occurs through two pathways
1- Passive non saturable Paracellular, Na+ independent pathway
the study revealed that passive occurs along concentration gradients through tight junction complexes (eg claudin and occludins )between cell membrane
animal data revealed that 65% to 80%of intestinal phosphate absorption occurs paracellularly and human data support the dominance of paracellular pathway particularly when phosphate concentration are high
2- Active saturable Transcellular, Na+ dependent pathway via sodium phosphate cotransporter (NaPi-IIb)
This new understanding of phosphate absorption pass ways
1-Acting on active pathway
a- EOS789 Drug an inhibitor of the sodium phosphate cotransporter Na pi 2b, and Pi t -1
b- Nicotinamide also seem to reduce phosphate -specific transcellular permeability by inihibition gut Napi 2b cotransporter is another potential hyperphosphatemia treatment but lacking large studies to support wide spreads use
2-acting on passive pathway
Tenapnor drug is another novel drug targeted phosphate absorption pass way
mechanism of action inhibits the sodium /hydrogen exchanger isoform 3(NHE3) in the GI tract
inhibition of NHE3 blocks paracellular phosphate permeability by reducing sodium absorption and causing conformational changes in ight junctional proteins
Tenapanor has been found to efficiently reduce phosphate level s in multiple clinical trial
All these novel drugs need multiple trial , solid study and comparison with other binders phosphate medication
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
Tow main intestinal pathways of phosphate absorption are therapeutic targets:
1.Transcellular pathway:
2.Paracellular pathway:
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?dietary phosphate is absorbed by
1-transcellular pathway (active process )
facilitated by the type 2 NaPi2b which saturated in patients with ESKD
2-paracellular patheay (passive ) non saaturated and occur through concentration gradients through tight junction complex between cell membranes
65% to 80 % of intestinal phosphate absorption occurs paracellularly
so new therapies targeting intestinal phosphate absorption pathways phase 1 trials of the novel drug an inhibitorof sodium phosphate cotransporter
tenapanor :inhibit the sodium /hydrogen exchanger in GI tract (paracellular patheay )
By blocking the NaHExchanger3 with tenapanor, the paracellular pathway which account for 60-80% of phosphat absorption is blocked or not more so effective.
This will lead to decreased phosphate absorption in gut. Tenapanor could be taken 2 time daily what lead to better adherence. In the study done patient could decrease their phosphate binders from 15 tablet a day to just 3.
That led to better compliance and better phosphate control.
The transcellular way through blocking NaPi2b with EOS789 led also to benefits.
There is an additive effect when we combine these drugs with phosphate binders.
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
1- Paracellular pathway: this is a passive process, according to the concentration gradient and it is responsible for about 80 % of intestinal phosphate absorption.it involves some proteins in the tight junctions between the colonic mucosal epithelial cells as Claudins. this pathway can be blocked by Tenapanor that enhance Na and water secretion and therefore decrease the transit time for passive absorption.
2- Transcellular pathway : this is an active process, against the concentration gradient and it is responsible for about 20 % of intestinal phosphate absorption. it involve a specific Na-Phosphate co transporter that can be blocked by the new phosphate binder, EOS789
How Intestinal phosphate absorption pathways could pave the way for novel therapies of phosphate control?
Tow main intestinal pathways of phosphate absorption are therapeutic targets:
1.Transcellular pathway:
2.Paracellular pathway: